Kirsten大鼠肉瘤病毒癌基因（KRAS）是最常见的癌基因之一，广泛存在于多种类型肿瘤中。由于细胞内三磷酸鸟苷（GTP）浓度较高，且KRAS蛋白缺乏“药理口袋”，早期KRAS被认定为“不可成药”靶点。2021年，首个KRAS^G12C抑制剂Sotorasib获批上市，用于治疗携带G12C突变的非小细胞肺癌患者。KRAS^G12D是KRAS家族中最常见的突变亚型，同年，针对该突变的首个抑制剂MRTX1133成功开发，目前已在肿瘤细胞体外模型及肿瘤异种移植模型中展现出显著的抗肿瘤活性。此外，单一药物治疗易引发耐药问题，MRTX1133的机制研究也证实了这一现象。总结MRTX1133在各类肿瘤中的最新机制研究进展及耐药相关问题，提出后续研究者可通过筛选关键耐药基因、开展联合治疗以缓解耐药，为小分子靶向药物研发及临床治疗策略优化提供新的思路。

Kirsten rat sarcoma viral oncogene homolog（KRAS） is one of the most common oncogenes, occurring in a variety of tumor types. Due to the high intracellular concentration of GTP and the lack of “druggable pocket” in KRAS protein, KRAS was historically considered an “undruggable” target. In 2021, the first KRAS^G12C inhibitor, Sotorasib, was approved for the treatment of patients with G12C mutated non-small cell lung cancer. KRAS^G12D is the most common KRAS mutation. In 2021, the first KRASG12D inhibitor, MRTX1133, was well developed and has demonstrated significant antitumor efficacy in both in vitro tumor cell models and xenograft tumor models. Additionally, as monotherapy frequently leads to drug resistance, similar challenges have been observed in mechanistic studies of MRTX1133. This review summarizes the latest mechanistic research and resistance mechanisms of MRTX1133 across various tumor types. Researchers are identifying key resistance genes and developing combination therapies to overcome drug resistance, thereby providing novel strategies for the development and clinical treatment of small molecule drugs.

R979.1

科技部国家科技资源共享服务平台，中国科学院战略生物资源技术支撑体系专项（CZBZX-1），中国科学院生物遗传资源库能力提升运行实施方案（E429A401X1T06）